Role of the Nervous System in Tumor Angiogenesis

Abstract

The development of cancer involves an intricate process, wherein many identified and unidentified factors play a role. Tumor angiogenesis, growth of new blood vessels, is one of the major prerequisites for tumor growth as tumor cells rely on adequate oxygen and nutrient supply as well as the removal of waste products. Growth factors including VEGF orchestrate the development of angiogenesis. In addition, nervous system via the release of neurotransmitters contributes to tumor angiogenesis. The nervous system governs functional activities of many organs, and, as tumors are not independent organs within an organism, this system is integrally involved in tumor growth and progression via regulating tumor angiogenesis. Various neurotransmitters have been reported to play an important role in tumor angiogenesis.

Keywords: Angiogenesis; Cancer; Nervous system; Neuro-cancer interaction; Neuropeptides; Neurotransmitters.

Fig. 1

Neurotransmitter signalling pathways in cancer angiogenesis. Neuro-cancer communication is through the release of neurotransmitters activating different signalling kinases which promote cancer progression via angiogenesis. ACh, acetylcholine; β2-AR, β₂-adrenergic receptor; cAMP, cyclic adenosine monophosphate; AKT, serine/threonine kinase or protein kinase B; DA, dopamine; DR, dopamine receptor; ERK_1/2, extracellular signal-regulated kinase; GABA, gamma-aminobutyric acid; GABA_A&B, gamma-aminobutyric acid receptor_A&B; Glu, glutamate; GRM1, glutamate receptor metabotropic 1; HIF-1, hypoxia inducible factor 1; 5-HT, 5-hydroxytryptamine (serotonin); 5-HTR, 5-hydroxytryptamine receptor (serotonin); MMP12, matrix metallopeptidase 12; mTOR, mammalian/mechanistic target of rapamycin; nAChR, nicotinic acetylcholine receptor; NE, norepinephrine; NPY, neuropeptide Y; PI3, phosphoinositide 3; PI3K, phosphoinositide 3-kinase; 4E–BP1, phosphorylated 4E binding protein 1; PKA, protein kinase A; p70S6K, serine/threonine kinase; VEGF, vascular endothelial growth factor; Y5R, neuropeptide receptor

Fig. 2

Growth factors intracellular signalling pathways in cancer angiogenesis. The binding of growth factors to their respective receptors (eg, EGF to EGFR) activates multiple kinase pathways which are involved in cancer angiogenesis. AKT, serine/threonine kinase or protein kinase B; ANG, angiogenin; BDNF, brain-derived neurotrophic factor; CEBPB, CCAAT/enhancer-binding protein beta; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK_1/2, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GSK3β, glycogen synthase kinase 3 beta; HGF, hepatocyte growth factor; c-Met, hepatocyte growth factor receptor; HIF-1α, hypoxia inducible factor 1 alpha; ICAM-1, intercellular adhesion molecule-1; MAPK, mitogen activated protein kinase; MEK_1/2, MAPK/ERK kinase; MMP2, matrix metallopeptidase 2; mTOR, mammalian/mechanistic target of rapamycin; NGF, nerve growth factor; NF-kB, nuclear factor-kappa B; NOS, nitric oxide synthase; PI3K, phosphoinositide 3-kinase; PKC-α, protein kinase C alpha; PLC-γ, phospholipase C-gamma; POU2F1, POU domain class 2 transcription factor 1; RAF, mitogen activated protein kinase; RAS, mitogen activated protein kinase; Tie2, angiopoietin receptor 2; TrkA, tropomyosin related kinase A; TrkB, tropomyosin related kinase B; VEGF, vascular endothelial growth factor